The invention relates to diagnostic markers for malignant cells.
Plasminogen, a serine proteinase precursor secreted by the liver, plays a pivotal role in dissolving blood clots (Saksela, Biochim. Biophys. Acta 823:35, 1985; Collen and Lijnen, Blood 78:3114, 1991). Cleavage of a specific Arg-Val peptide bond by either tissue-type or urokinase-type plasminogen activator along with autocatalytic removal of an N-terminal preactivation peptide produces the active two-chain proteinase plasmin. Plasmin is capable of attacking fibrin, a principal component of clots, thereby facilitating clot lysis (Robbins et al, J. Biol. Chem. 248:7242, 1973; Hoylaerts et al., J. Biol. Chem. 257:2912, 1982; Holvoet et al., J. Biol. Chem. 260:12106, 1985). In addition to its well-characterized thrombolytic capability, plasmin has been implicated along with other proteinases as a mediator of tissue remodeling during development (Matrisian, Trends Genet. 6:121, 1990), cartilage destruction in osteoarthritis (Eeckhout and Vaes, Biochem. J. 166:21, 1977; Werb et al., N. Engl. J. Med. 269:1017, 1977; Cruwys et al., J. Pharmacol. 100:631, 1990; Treadwell et al., J. Orth. Res. 9:309, 1991), and basement membrane invasion by metastatic tumor cells (Saksela, 1985, Supra; Tryggvason et al., Biophys. Acta 907:191, 1987; Moscatelli and Rifkin, Biochem. Biophys. Acta 948:67, 1988; Liotta et al., Cell 64:327, 1991).
Plasminogen is composed of an N-terminal preactivation peptide, a central section containing five adjacent homologous domains called kringles (Patthy et al., FEBS Lett. 171:131, 1984), and a C-terminal catalytic region (Wiman and Wallen, Eur. J. Biochem. 50:489, 1975; Wiman and Wallen, Eur. J. Biochem. 58:539, 1975; Wiman, Eur. J. Biochem. 76:129, 1977; Sottrup-Jensenet al., Prog. Chem. Fibrinol. Thrombol. 3:191, 1978).
A single gene for plasminogen has been reported from which the liver mRNA is derived (Forsgren et al., FEBS Lett. 213:254, 1987; Peterson et al., J. Biol. Chem. 265:6104, 1990). Recent duplications of at least portions of the plasminogen gene have occurred. For example, the apolipoprotein (a) gene contains extremely homologous domains, with similarity at the nucleotide level of greater than 90% in some areas (McLean et al., Nature 330:132, 1987). The plasminogen gene family also includes several coagulation proteins as well as hepatocyte growth factor (Miyazawa et al., Biochem. Biophys. Res. Commun. 163:967, 1989, Nakamura et al., Nature 342:440-443, 1989).